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Process for preparation of beta -lactams at constantly high concentration of reactants

a technology of reactants and betalactams, which is applied in the field of process for preparing betalactams at constantly high concentration of reactants, can solve the problems of enzymes present that may decompose the starting acylating agent, and the reaction typically involves costly steps, so as to improve the yield of beta-lactam derivatives, improve the molar ratio, and reduce the effect of acylating agent degradation

Inactive Publication Date: 2000-04-11
GIST BROCADES NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

are, Inter alia, as Follows1) An improved molar ratio between the amount of .beta.-lactam derivative which can be recovered from the reaction mixture and the amount of the acid form of the acylating agent, compared with this ratio for the known processes, is obtained. This improvement has direct impact on the economy of the process due to the reduced consumption of acylating agent versus .beta.-lactam derivative which can be recovered from the reaction mixture. This improvement also has an indirect impact on the economy of the process due to the lower amount of the acid form of the acylating agent which is to be removed from the desired .beta.-lactam derivative.2) An increased yield of the .beta.-lactam derivative is obtained.3) An increase in the productivity of the .beta.-lactam derivative is obtained. This productivity is defined as the amount of .beta.-lactam derivative which can be recovered per time unit per volume unit of the reaction mixture.

Problems solved by technology

These reactions typically involve costly steps such as sub zero degree Celcius conditions and organic solvents like methylene chloride and silylation reagents.
In addition, the enzyme present may decompose the starting acylating agent.

Method used

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  • Process for preparation of beta -lactams at constantly high concentration of reactants

Examples

Experimental program
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example 1

Enzymatic Preparation of Amoxicillin from D-HPGM and 6-APA

The equipment for this experiment consisted of (see FIG. 1) a thermostated reactor having a volume of 1.5 liters, equipped with a three-bladed impeller and a sieve with slots 180 .mu.m (open area about 32%) The reactor was connected to an autotitrator system using 4 M sulphuric acid as titrand. A valve was positioned at the outlet of the reactor. The outlet of the valve was connected via a pump to a basket centrifuge equipped with a polypropylene bag having a density of 1-5 .mu.m. The outlet from the centrifuge was connected via a pump to a feed tank equipped with a stirrer and a glass sinter bottom. The outlet from the feed tank was connected via a pump to the reactor.

A mixture consisting D-HPGM (36.2 g, 200 mmol) and 6-APA (43.2 g, 200 mmol) in 800 ml water was added to the reactor with the bottom valve closed. The stirring was started. Immobilized Penicillin G acylase (26250 U, size 200-500 .mu.m) made up to 200 ml was add...

example 2

Enzymatic Preparation of Amoxycillin from D-HPGA and 6-APA

The equipment for this experiment is described in example 1.

A mixture consisting of D-HPGA (20.0 g, 120 mmol) and 6-APA in 800 ml water, which was adjusted at a pH value of 6.0 by adding 4 M ammonium hydroxide, was added to the reactor with the bottom valve closed. The stirring was started. Immobilized Penicillin G acylase (26250 U, size 200-500 .mu.m) made up to 200 ml was added to the reactor. The pH value was maintained at 6.0. The reaction temperature was about 20.degree. C. Under these conditions the reaction mixture was almost saturated with D-HPGA and 6-APA. Then the bottom valve was opened allowing the reaction mixture from the reactor to enter the centrifuge. Thereafter, the mother liquor from the centrifuge was pumped into the feed tank wherein D-HPGA (20.0 g, 120 mmol) and 6-APA (20.0 g, 92.5 mmol) were loaded. The total volume of the suspension in the feed tank was kept at about 75 ml. A flow of about 100 ml / min w...

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Abstract

PCT No. PCT / EP95 / 02876 Sec. 371 Date Feb. 19, 1997 Sec. 102(e) Date Feb. 19, 1997 PCT Filed Jul. 18, 1995 PCT Pub. No. WO96 / 02663 PCT Pub. Date Feb. 1, 1996An improvement for enzymatically syhnthesizing a beta -lactam compound is presented. The improvement comprises catalyzing the acylation of an amino beta -lactam with an acylating agent for at least 5 hours with an amidase or acylase, wherein the concentration of each reactant is constantly higher than 70% of the lowest value of the saturated concentration of both reactants.

Description

This invention relates to a an improved process for preparation of .beta.-Lactam derivatives by enzymatic acylation of the parent amino .beta.-lactam with an acylating agent.Today, semisynthetic .beta.-lactam derivatives such as ampicillin, amoxicillin, cefaclor, cephalexin, cephadroxil and cephaloglycin are, in an industrial scale, prepared by chemical methods, for example by reacting an amino .beta.-lactam such as 6-aminopenicillanic acid, usually having its carboxyl group protected, with an activated side chain derivative, followed by the removal of the protecting group by hydrolysis. For example, ampicillin (6-D-.alpha.-aminophenylacetamido-penicillanic acid) can be prepared by reacting 6-APA, having a suitable protected carboxyl group, with D-phenylglycine acid chloride, followed by removal of the protecting group by hydrolysis. These reactions typically involve costly steps such as sub zero degree Celcius conditions and organic solvents like methylene chloride and silylation r...

Claims

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Application Information

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IPC IPC(8): C12P35/04C12P35/00C12P37/00C12P37/04
CPCC12P37/04C12P35/04
Inventor CLAUSEN, KIMDEKKERS, ROCUS M.
Owner GIST BROCADES NV
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